4.1. Therapeutic indications

Picato is indicated for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults.

4.2. Posology and method of administration

Posology

Actinic keratosis on the trunk and extremities in adults

One tube of Picato 500 mcg/g gel (containing 235 mcg ingenol mebutate) should be applied once daily to the affected area for 2 consecutive days.

Optimal therapeutic effect can be assessed approximately 8 weeks after treatment.

A repeat treatment course of Picato can be given if an incomplete response is seen at a follow-up examination after 8 weeks or if lesions that are cleared at this examination recur in subsequent examinations.

Paediatric population

There is no relevant use of Picato in the paediatric population.

Elderly population

No dose adjustment is required (see section 5.1).

Immunocompromised patients

Clinical data on treatment in immunocompromised patients is not available, but systemic risks are not expected since ingenol mebutate is not absorbed systemically.

Method of administration

The content of one tube covers a treatment area of 25 cm2 (e.g. 5 cm x 5 cm). The tube is for single use only and should be discarded after use (see section 6.6).

The gel from the tube should be squeezed onto a fingertip and spread evenly over the entire treatment area, allowing it to dry for 15 minutes. The content of one tube should be used for one treatment area of 25 cm2.

For single use only.

For treatment of the neck:

If more than half of the treatment area is located in the upper part of the neck, Picato 150 mcg/g gel should be used at the posology for face and scalp. If more than half of the treatment area is located in the lower part of the neck, Picato 500 mcg/g gel should be used at the posology for trunk and extremities.

If an area on the face or scalp and another area on the trunk or extremities are simultaneously treated, then patients should be advised to ensure they use the appropriate strengths. Care should be exercised not to apply the Picato 500 mcg/g gel on the face or scalp as this could lead to a higher incidence of local skin responses.

Patients should be instructed to wash their hands with soap and water, immediately after applying Picato, and between topical applications if two different areas require different strengths. If treating the hands, only the fingertip which is used for applying the gel should be washed.

Washing and touching the treated area should be avoided for a period of 6 hours after application of Picato. After this period, the treatment area may be washed using mild soap and water.

Picato should not be applied immediately after taking a shower or less than 2 hours before bedtime.

The treated area should not be covered with occlusive bandages after Picato is applied.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Eye exposure

Contact with the eyes can cause chemical conjunctivitis and corneal burns. Patients should wash their hands thoroughly after applying the gel and following any contact with the treated area, to avoid inadvertent transfer of the gel to the eyes. If accidental exposure occurs, the eyes should be flushed immediately with large amounts of water, and the patient should seek medical care as soon as possible. Eye disorders such as eye pain, eyelid oedema and periorbital oedema should be expected to occur after accidental eye exposure of Picato (see section 4.8).

Ingestion

Picato must not be ingested. If accidental ingestion occurs the patient should drink plenty of water and seek medical care.

General

Administration of Picato is not recommended until the skin is healed from treatment with any previous medicinal product or surgical treatment and should not be applied to open wounds or damaged skin where the skin barrier is compromised.

Picato should not be used near the eyes, on the inside of the nostrils, on the inside of the ears or on the lips.

Local skin responses

Local skin responses such as erythema, flaking/scaling, and crusting should be expected to occur after cutaneous application of Picato (see section 4.8). Localised skin responses are transient and typically occur within 1 day of treatment initiation and peak in intensity up to 1 week following completion of treatment. Localised skin responses typically resolve within 2 weeks of treatment initiation when treating areas on the face and scalp and within 4 weeks of treatment initiation when treating areas on the trunk and extremities. Treatment effect may not be adequately assessed until resolution of local skin responses.

Sun exposure

Studies have been conducted to assess the effects of UV irradiation of the skin following single and multiple applications of ingenol mebutate gel, 100 mcg/g. Ingenol mebutate gel did not demonstrate any potential for photo irritation or photo allergic effects. However, due to the nature of the disease, excessive exposure to sunlight (including sunlamps and tanning beds) should be avoided or minimised.

Keratoacanthoma, basal cell carcinoma, Bowen's disease, squamous cell carcinoma

Reports of keratoacanthoma, basal cell carcinoma, Bowen's disease, squamous cell carcinoma occurring within the treatment area with a time to onset ranging from weeks to months following use of ingenol mebutate gel have been received from a post-authorisation clinical trial (see section 5.1) and post-marketing. Ingenol mebutate should be used with caution in patients with a history of cutaneous malignancy. Health care professionals should advise patients to be vigilant for any lesions developing within the treatment area and to seek medical advice immediately should any occur.

Management of actinic keratosis

Lesions clinically atypical for actinic keratosis or suspicious for malignancy should be biopsied to determine appropriate treatment.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Interactions with systemically absorbed medicinal products are considered unlikely as Picato is not absorbed systemically.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of ingenol mebutate in pregnant women. Animal studies showed slight embryo-fetal toxicity (see section 5.3). Risks to humans receiving cutaneous treatment with ingenol mebutate are considered unlikely as Picato is not absorbed systemically. As a precautionary measure, it is preferable to avoid the use of Picato during pregnancy.

Breast-feeding

No effects on the breastfed newborn/infant are anticipated as Picato is not absorbed systemically. The nursing mother should be instructed that physical contact between her newborn/infant and the treated area should be avoided for a period of 6 hours after application of Picato.

Fertility

No fertility studies have been performed with ingenol mebutate.

4.7. Effects on ability to drive and use machines

Picato has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions are local skin responses including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration at the application site of ingenol mebutate gel, see table 1 for MedDRA terms. Following the application of ingenol mebutate, most patients (>95%) experienced one or more local skin response(s). Infection at the application site has been reported when treating face and scalp.

Tabulated list of adverse reactions

Table 1 reflects exposure to Picato 150 mcg/g or 500 mcg/g in 499 patients with actinic keratosis treated in four vehicle controlled phase 3 studies enrolling a total of 1,002 patients and post-marketing reports. Patients received field treatment (area of 25 cm2) with Picato at concentrations of 150 mcg/g or 500 mcg/g or vehicle once daily for 3 or 2 consecutive days respectively.

The table below presents adverse reactions by MedDRA system organ class and anatomical location.

Frequencies have been defined according to the following convention:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions by MedDRA System Organ Classification

Frequency

System Organ Class

Face and scalp

Trunk and extremities

Infections and infestations

Application site pustules

Very common

Very common

Application site infection

Common

Immune system disorders

Hypersensitivity (including angioedema)

Uncommon

Uncommon

Nervous system disorders

Headache

Common

Eye disorders*

Eye lid oedema

Common

Periorbital oedema

Common

Chemical conjunctivitis, corneal burn**

Uncommon

Uncommon

Eye pain

Uncommon

General disorders and administration site conditions

Application site erosion

Very common

Very common

Application site vesicles

Very common

Very common

Application site swelling

Very common

Very common

Application site exfoliation

Very common

Very common

Application site scab

Very common

Very common

Application site erythema

Very common

Very common

Application site pain***

Very common

Common

Application site pruritus

Common

Common

Application site irritation

Common

Common

Application site discharge

Uncommon

Application site paraesthesia

Uncommon

Uncommon

Application site ulcer

Uncommon

Uncommon

Application site pigmentation changes

Uncommon

Uncommon

Application site warmth

Uncommon

Application site scarring

Rare

Rare

*: Application site swelling on the face or scalp may gravitate to the eye area

**: Accidental eye exposure: Post-marketing reports of chemical conjunctivitis and corneal burn in connection with accidental eye exposure have been received (see sections 4.2 and 4.4 for prevention of eye exposure)

***: Including application site burning.

Description of selected adverse reactions

The incidence of local skin responses that occurred at an incidence >1% in both the 'face/scalp' and the 'trunk/extremities', respectively are: application site erythema (94% and 92%), application site exfoliation (85% and 90%), application site scab (80% and 74%), application site swelling (79% and 64%), application site vesicles (13% and 20%), application site pustules (43% and 23%) and application site erosion (31% and 25%).

Severe local skin responses occurred with an incidence of 29% on the face and scalp and with an incidence of 17% on the trunk and extremities. The incidence of severe local skin responses that occurred at an incidence >1% in both the 'face/scalp' and the 'trunk/extremities', respectively are: application site erythema (24% and 15%), application site exfoliation (9% and 8%), application site scab (6% and 4%), application site swelling (5% and 3%) and application site pustules (5% and 1%).

Long-term follow up

A total of 198 patients with complete clearance at day 57 (184 treated with Picato and 14 treated with vehicle) were followed for additionally 12 months. In another study, 329 patients who were initially treated with cryotherapy on the face/scalp were randomised after three weeks to either Picato 150 mcg/g (n=158) or vehicle (n=150) for 3 days in the same area. 149 patients in the Picato group and 140 in the vehicle group were followed for 12 months. In a later study 450 patients were initially treated with Picato 150 mcg/g, of these 134 patients were randomised to a second treatment course of Picato 150 mcg/g and the patients followed for up to 12 months after the first treatment.

These results did not change the safety profile of Picato (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Overdosing of Picato could result in an increased incidence of local skin responses. Management of overdose should consist of treatment of clinical symptoms.